Alcoholic hepatitis (AH) has a high morbidity and mortality with a four year survival ranges from 35% to 60 %, dependent on the presence or absence of cirrhosis. Despite over 40 years of research on AH, there is still no FDA approved treatment for this disease. The most commonly used off-label drugs for AH are corticosteroids and pentoxifylline. Unfortunately, even patients with AH treated with corticosteroids have a 6 month mortality of 40%. These poor clinical outcomes are due, in large part, to an incomplete understanding of the pathophysiology of alcohol-mediated liver injury. Therefore, there is an urgent need for effective new therapies for this pernicious disease. This multicenter study will be a collaborative effort of four medical centers (Cleveland Clinic, University of Louisville, UT Southwestern, and University of Massachusetts) with its ultimate goal of transforming the clinical treatment of AH by rapidly translating novel and innovative basic science discoveries into clinical practice. In the first 2.5 years of the grant, two clinical trials will test the hypohesis that disruption of the normal gut-barrier function, over-activation of the inflammatory cascade, and innate immune activation are the primary elements of the complex pathogenesis of AH. In patients with severe AH, the first trial will compare a novel drug combination of anakinra (an inhibitor of IL-1 activity), pentoxifylline (a phosphodiesterase inhibitor that suppresses the inflammatory cytokine cascade), and zinc (which improves gut-barrier function) with the current standard of care therapy of treatment with corticosteroids. The second trial will compare probiotics (to improve gut-barrier function) to placebo in patients with moderate AH. The primary outcomes of both clinical trials will be 6 month mortality. Both trials will also supply specimens o the translational/basic science components of this UO1 consortium to identify novel biomarkers and altered pharmacogenetics that predict disease severity and response to pharmacologic therapy as well as to identify unique drug targets for novel treatments for AH. These new discoveries will then be translated rapidly to clinical testing in the last 2.5 years of the grant.A biorepository of the collected clinical data and patient samples will also be established that will be an important national resource for transforming clinical practice for the treatment of AH. PUBLIC HEALTH RELEVANCE: Animal studies have increased the knowledge of mechanisms of alcohol induced liver injury. Despite this knowledge, the morbidity and mortality of AH has not improved and there remains a pressing need for new therapeutic strategies and prognostic indicators. Translational studies between basic science and clinical testing have been lacking. There also have been limited trials of combination therapies even though AH has a complex pathophysiology involving multiple mechanisms of injury. Therefore, the highly innovative therapies proposed in our clinical trials and the ability of this consortium to rapidly translate basic science approaches into clinical practice makes the grant highly relevant to the improved clinical care of patients with AH.